React-pxe: a consensus on diagnosis and future research concerning pseudoxanthoma elasticum (PXE)

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder described more than 150 years ago in which calcification and fragmentation of the elastic fibers result in a variety of symptoms which differ greatly in presentation and severity between patients. The diagnosis of PXE can still be made in many patients based on clinical presentation. However, in the advent of genetic screening that followed upon the identification of the first causal gene, ABCC6, milder cases of PXE or patients with a less typical onset of disease surfaced. Moreover, it became clear in the last years that PXE has at least one allelic disorder which can also result from (identical) ABCC6 or ENPP1 pathogenic variants, namely generalized arterial calcification of infancy (GACI). These recent evolutions lead to challenges in making the correct diagnosis in a given number of patients. As emerging possibilities to treat PXE require a definite diagnosis, a critical re-appraisal of the diagnostic criteria for PXE - taking into account new clinical, biochemical and molecular characteristics - appeared to be necessary. The REACT-PXE (Research, Education and Advanced Care Teams for PXE) Consortium - gathering most European experts on PXE - has been established to take on this task as a first step in updating the management of PXE. This paper presents an updated, evidence-based definition of PXE, revised diagnostic criteria, "red flags" for considering PXE, and a patient-centered approach to identifying meaningful outcomes. All skin, ocular, vascular and other disease manifestations are addressed and illustrated, followed by specific chapters on molecular genetics and biological alterations. All these efforts are designed to improve disease management, consider future treatment for all patients, with or without molecular definition of their condition, enhance patient care, and inform for future research directions.